Flavonoids improve neurotransmitters for Parkinson's treatment: mechanism and therapeutic potential

Parkinson's disease (PD) is recognized as the second most common neurodegenerative disorder worldwide, and it stands out as one of the neurological conditions exhibiting the fastest rise in prevalence, disability, and economic consequences. While the degeneration of dopaminergic neurons and the depletion of striatal dopamine are fundamental to the classic motor symptoms of PD, growing evidence suggests that PD is a multifaceted multisystem disorder marked by extensive impairment across various neurotransmitter systems. Beyond dopaminergic impairment, serotonergic, glutamatergic, γ-aminobutyric acid (GABA)ergic and cholinergic pathways are profoundly disrupted during disease progression, contributing to motor and non-motor symptoms that respond poorly to dopamine-centred therapies. These limitations underscore an unmet need for multi-target therapeutic strategies capable of restoring broader neurotransmitter homeostasis. Flavonoids represent a varied group of polyphenolic compounds sourced from plants and have been recognized as potential neuropharmacological candidates due to their multifaceted biological activities and advantageous safety characteristics. Flavonoids not only possess antioxidant and anti-inflammatory characteristics, but they also influence intracellular signaling pathways, mitochondrial activity, neuroinflammation, and synaptic plasticity. Additionally, many of these compounds have the ability to traverse the blood-brain barrier. A growing body of preclinical evidence suggests that representative flavonoids-including baicalein, quercetin, apigenin, luteolin and EGCG-exert neuroprotective effects in experimental PD models by preserving dopaminergic neurons, attenuating α-synuclein pathology, modulating monoamine metabolism and suppressing glutamate-driven excitability.In this Review, we synthesize current evidence that flavonoids can ameliorate neurotransmitter dysfunction in PD. Focusing on dopamine, serotonin, glutamate and acetylcholine, we integrate experimental findings to highlight the multi-target regulatory capacity of flavonoids. We also discuss key pharmacokinetic limitations, nanodelivery strategies, toxicological considerations and translational challenges.